Loss-of-function mutations in ADCY3 cause monogenic severe obesity

• Published in: Nature genetics Vol. 50; no. 2; pp. 175 - 179
• Main Authors: Saeed, Sadia, Bonnefond, Amélie, Tamanini, Filippo, Mirza, Muhammad Usman, Manzoor, Jaida, Janjua, Qasim M., Din, Sadia M., Gaitan, Julien, Milochau, Alexandra, Durand, Emmanuelle, Vaillant, Emmanuel, Haseeb, Attiya, De Graeve, Franck, Rabearivelo, Iandry, Sand, Olivier, Queniat, Gurvan, Boutry, Raphaël, Schott, Dina A., Ayesha, Hina, Ali, Muhammad, Khan, Waqas I., Butt, Taeed A., Rinne, Tuula, Stumpel, Connie, Abderrahmani, Amar, Lang, Jochen, Arslan, Muhammad, Froguel, Philippe
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-02-2018; Nature Publishing Group
• Subjects: 631/208/2489; 631/208/514; Adenylate cyclase; Agriculture; Animal Genetics and Genomics; Appetite; Binding sites; Biomedical and Life Sciences; Biomedicine; Body mass index; Cancer Research; Children; Diabetes; DNA methylation; Energy balance; Families & family life; Gene Function; Genes; Genomes; Homeostasis; Human Genetics; Insulin resistance; Kinases; Leptin; Letter; Life Sciences; Melanocortin; Mutation; Obesity; Pharmacology; Proteins; Pakistan
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-017-0023-6

Study of monogenic forms of obesity has demonstrated the pivotal role of the central leptin–melanocortin pathway in controlling energy balance, appetite and body weight
1
. The majority of loss-of-function mutations (mostly recessive or co-dominant) have been identified in genes that are directly involved in leptin–melanocortin signaling. These genes, however, only explain obesity in <5% of cases, predominantly from outbred populations
2
. We previously showed that, in a consanguineous population in Pakistan, recessive mutations in known obesity-related genes explain ~30% of cases with severe obesity
3
–
5
. These data suggested that new monogenic forms of obesity could also be identified in this population. Here we identify and functionally characterize homozygous mutations in the
ADCY3
gene encoding adenylate cyclase 3 in children with severe obesity from consanguineous Pakistani families, as well as compound heterozygous mutations in a severely obese child of European-American descent. These findings highlight ADCY3 as an important mediator of energy homeostasis and an attractive pharmacological target in the treatment of obesity.
Genetic analysis of children with severe obesity identifies mutations in the
ADCY3
gene (encoding adenylate cyclase 3). These variants are rare in public databases and affect the functional activity of the protein, indicating that ADCY3 is a potential pharmacological target for obesity treatment.